Important and yet unanswered questions regarding antiviral therapies for HIV are whether drug-resistant mutants are pathogenic and whether their emergence causes further disease progression or failure of therapy. We previously isolated a drug-resistant mutant from a simian immunodeficiency virus (SIV) -infected macaque after 8 months of 3'-azido-3'-deoxythymidine (AZT) therapy. Genetic analysis of this AZT-resistant SIV revealed no mutations at the sites most commonly responsible for AZT-resistance in HIV-1 infected people. However, a substitution of methionine (M) for the wild-type glutamine (Q) was found at amino acid position 151 which is in a highly conserved region of the reverse transcriptase (RT) palm subdomain, thought to be part of the RT active site. This Q151M mutation has recently also been described for HIV-1 isolates from patients receiving AZT in combination with other antiviral drugs and is associated with multiple drug resistance. Our AZT-resistant SIV mutant also shows multiple drug resistance. To evaluate the virulence of this mutant virus, four newborn macaques were inoculated intravenously with a biological clone of this AZT-resistant SIV. Two animals were also treated with AZT. All four animals became persistently infected, and the virus isolated from these animals was AZT-resistant. One untreated animal had persistently high viremia, no SIV-specific antibody responses, and died at 12 weeks with severe symptoms of AIDS. One AZT-treated animal died with AIDS at 8 months. The remaining two animals are alive at 14 months, but have persistent viremia, severely depressed CD4/CD8+ T cell ratios, reduced absolute CD4+ T cells, and poor weight gain. These results demonstrate that a Q151M mutation in SIV RT is compatible with full virulence, and underscores the problem of drug resistance in antiviral therapy. *KEY* Pediatric simian AIDS, Oral SIV transmission, Antiretroviral drug resistance, 3'-azido-3'-deoxythymidine